OBJECTIVE To study the effectiveness of high-frequency ventilation (HFV) for the treatment of pediatric patients with acute severe respiratory failure. METHODS Post hoc analysis of retrospectively and prospectively acquired data. METHODS Tertiary pediatric ICU. METHODS Twelve patients, ages 4 months to 15 years, who developed acute severe respiratory failure from diverse causes. METHODS Patients were treated with synchronized intermittent mandatory ventilation (SIMV) using moderate positive end-expiratory pressure (PEEP) and supplemental oxygen prior to HFV therapy. Ten of 12 patients required one or more medications to modulate preload, inotropy, and/or afterload. All patients were invasively monitored for arterial BP and arterial blood gases, and they were noninvasively monitored for oxygen saturation, end tidal or transcutaneous carbon dioxide, and electrocardiography. RESULTS Severity of respiratory failure was reflected by median values of pH of 7.34, lung compliance of 0.41 ml/cm H2O/kg, P(A-a)O2 of 553 mm Hg, oxygenation index (OI) of 28, and ventilation index of 102. Significant improvement in pH, PaCO2, PaO2, OI, and P(A-a)O2 was demonstrated early in the course of HFV (p < 0.05). Seven of the patients (58 percent) were survivors. CONCLUSIONS These data suggest that HFV may offer significant benefit as a rescue modality for patients with severe respiratory failure refractory to SIMV strategies early in the course of the disease process.